title: Lentiviral mediated expression of a NGF-soluble Nogo receptor 1 fusion protein promotes axonal regeneration.
abstract: Nogo receptor 1 (NgR1) mediates the inhibitory effects of several myelin-associated inhibitors (MAIs) on axonal regeneration in the central nervous system. A truncated soluble NgR1 (sNgR) has been reported to act as a decoy receptor to block the actions of MAIs. In this study, we fused the sNgR to nerve growth factor (NGF) and used NGF as a carrier to deliver sNgR to the intercellular space to neutralize MAIs. NGF in NGF-sNgR remained biologically active and induced sprouting of calcitonin gene related peptide containing axons when expressed in the spinal cord using a lentiviral vector (LV). Secreted NGF-sNgR promoted neurite outgrowth of dissociated dorsal root ganglion neurons on myelin protein substrate. In a rat dorsal column transection model, regenerating sensory axons were found to grow into the lesion cavity in animals injected with LV/NGF-sNgR, while in animals injected with LV/GFP or LV/NGF-GFP few sensory axons entered the lesion cavity. The results indicate that NGF-sNgR fusion protein can reduce the inhibition of MAIs and facilitate sensory axon regeneration. The fusion constructs may be modified to target other molecules to promote axonal regeneration and the concept may also be adapted to develop gene therapy strategies to treat other disorders.
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fangyou
authors.initials: F
authors.lastname: Gao
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wu
authors.forename: Pouria
authors.initials: P
authors.lastname: Moshayedi
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Habib
authors.initials: H
authors.lastname: Ellamushi
authors.forename: John
authors.initials: J
authors.lastname: Yeh
authors.forename: John V
authors.initials: JV
authors.lastname: Priestley
authors.forename: Xuenong
authors.initials: X
authors.lastname: Bo
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D016086:Lentivirus / Q000235:genetics / Q000502:physiology*; D008297:Male; D004676:Myelin Basic Protein / Q000378:metabolism; D009185:Myelin Proteins / Q000008:administration & dosage* / Q000096:biosynthesis; D020932:Nerve Growth Factor / Q000096:biosynthesis / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D016501:Neurites / Q000187:drug effects; D000070798:Nogo Proteins; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D012701:Serotonin / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000150:complications / Q000628:therapy*
chemical_list: D004676:Myelin Basic Protein; D009185:Myelin Proteins; D000070798:Nogo Proteins; D011993:Recombinant Fusion Proteins; C000603197:Rtn4 protein, rat; D012701:Serotonin; D020932:Nerve Growth Factor; D015740:Calcitonin Gene-Related Peptide
keywords: Axon regeneration; Gene therapy; Lentiviral vector; Nerve growth factor; Nogo receptor; Spinal cord injury